Gel-forming liquid carrier composition

ABSTRACT

A carrier composition that is a liquid at or below room temperature forms a high viscosity layer or gel at body temperature, which comprises a water-soluble, nonionic cellulose ether having a cloud point not higher than 40° C., a charged surfactant and optional additives in water. The carrier composition can be used for oral or local administration of a pharmacologically active substance to the skin, mucous membrane, the eye or a body cavity.

The present invention refers to a carrier composition which is liquid ator below room temperature and forms a high viscosity layer or gel atbody temperature. The invention also refers to a pharmaceuticalcomposition containing a pharmacologically active substance incombination with said carrier composition. Said compositions can beorally or locally administrated to the skin, the mucous membrane, theeye or a body cavity.

For local administration of a drug to different regions of the humanbody in order to obtain a local or systemic pharmacological effect thedrug is normally combined with a semi-solid or liquid carrier tooptimize drug uptake and administration. For many non-parental routes ofadministration there is often a need to prolong the duration ofresidence of the dosage form. This can be achieved by using abioadhesive system, wherein the dosage form, by virtue of containing abioadhesive polymer, adheres to the skin or the mucosa until the polymerdissolves or is replaced.

Polymers having bioadhesive properties are for instance water-solublecellulose derivatives, such as sodium carboxymethyl cellulose, andpolyacrylic acids, which are used in many pharmaceutical preparations toimprove the contact between drug and body. If these polymers areadministrated in liquid form they are, however, removed too fast. If asolid or viscous dosage form is used for local administration of drugs,there will on the other hand be limitations in the routes ofadministration and use in clinical practice.

Ophthalmic drugs delivered topically to the eye commonly have a lowbioavailability. Rapid loss of the instilled drug via drainage throughthe drainage apparatus has a considerable influence. This loss leads toa short contact time between drug and cornea, making the drug lessavailable for absorption into the eye. A well-known approach to improvethe bioavailability of topically applied drugs is to prolong theircorneal contact time. Improved uptake has been achieved by usingvehicles containing viscosity-increasing polymers such as the cellulosederivatives, polyvinyl alcohol and polyvinylpyrrolidone. It ispostulated that the increased viscosity results in reduced drainage ofthe instilled preparation, thereby increasing the bioavailability of thedrug.

Thermogelling pharmaceutical preparations are described in for instanceU.S. Pat. Nos. 4,478,822, 4,474,751, 4,474,752 and 4,474,753. Saidpatents refer to a drug delivery system which at room temperature hasthe properties of a liquid, but forms a semi-solid gel at human bodytemperatures. The compositions to be administered comprise 10 to 50% byweight of a polymer, which is a tetra-substituted derivative of certaindiamines containing approximately 40 to 80% poly(oxyethylene) andapproximately 20 to 60% poly(oxypropylene), as a drug delivery vehicle.In this system the gel transition temperature and/or the rigidity of thegel can be modified by adjustment of the pH.

Other systems are known in which the gelling is induced by an increasein the amount of electrolytes or a change in pH.

It has now surprisingly been found that certain water-soluble nonioniccellulose ethers in combination with a charged surfactant and optionaladditives in water have the property of being liquid at room temperatureand forming a gel when warmed to body temperature. The process isreversible. These cellulose ethers also have been shown to haveexcellent bioadhesive properties. Such characteristics can be utilizedfor specialized drug delivery. The drug can be introduced on or into thebody as a solution which will gel and adhere to body tissue just bymeans of the raise in temperature--no pH gradients or high electrolytecontents are required for the gelling.

The carrier composition of the invention is characterized in comprisinga water-soluble, nonionic cellulose ether having a cloud point nothigher than 40° C., preferably not higher than 35° C., a chargedsurfactant, and optional additives in water.

The carrier composition of the invention is also characterized incomprising a very low polymer concentration, that is the combinedconcentration of the cellulose ether and the surfactant is below 3% byweight, and preferably 0.5-1.5% by weight.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph demonstrating release rate of timolol maleate fromdifferent carrier systems.

FIG. 2 is a graph demonstrating in vitro release profile of insulin froma carrier system of the present invention.

FIG. 3 is a graph demonstrating in vivo release profile of insulin froma carrier system of the present invention.

BEST AND VARIOUS MODES FOR CARRYING OUT INVENTION

The nonionic cellulose ethers in the composition of the invention arebased on cellulose which has been chemically modified in order to attainsolubility in water by substitution of various groups onto the cellulosebackbone. The types and numbers of substituents should be chosen in sucha way as to give the cellulose ether a limited solubility with respectto temperature increases. Thus aqueous solutions of the cellulose ethershave a particular temperature above which a two-phase system is formed,which initially causes a strong light scattering and thus the system hasa cloudy appearance--this temperature is commonly referred to as thecloud point (CP) temperature.

Cloud point (CP) temperatures are determined on a Mettler FP5+FP51spectrophotometer. The sample solution (1.0 wt % aqueous cellulose ethersolution in a capillary tube) is heated at a rate of 10° C./min. The CPis then graphically determined as the break-point in the recordedabsorbance-versus-time curve.

In order to be liquid at room temperature and gel at body temperature,that is about 37° C., the cellulose ethers should have a CP not higherthan 35° C. If it is sufficient that a high viscosity layer is formed,the cloud point could be up to 40° C.

The properties of the cellulose ethers are determined by the type ofsubstituents and also by their number and distribution along themolecule.

The most appropriate cellulose derivatives are nonionic, where alkyland/or hydroxyalkyl groups are attached to the anhydroglucose units byether linkages, that is alkyl hydroxyalkyl celluloses, wherein the alkylgroups have from 1 to 4 carbon atoms.

Representative cellulose ethers are methyl cellulose (MC), methylhydroxyethyl cellulose (MHEC), methyl hydroxypropyl cellulose (MHPC),ethyl hydroxyethyl cellulose (EHEC), and hydroxypropyl cellulose (HPC).These polymers all have substituents that are either nonpolar (e.g.methyl) or slightly polar (e.g. hydroxyethyl), which in combination withthe hydrophilic cellulose backbone give rise to an amphiphilic polymer.

A preferred cellulose ether is EHEC, having the chemical formula

    [C.sub.6 H.sub.7 O.sub.2 (OH).sub.x (OC.sub.2 H.sub.5).sub.y [O(CH.sub.2 CH.sub.2 O).sub.m H].sub.z ].sub.n

where n is the degree of polymerisation, y is the degree of ethylsubstitution (DS_(ethyl)), and (m+z) is the molar hydroxyethyl (ethyleneoxide; EO) substitution (MS_(EO)). The average values of y and (m+z)could range from 1.2 to 2.5 and from 0.5 to 1.5, respectively; theactual values are dependent on n and the heterogeneity of substitution.

The substitution of EHEC is thus characterized by the values DS_(ethyl)and MS_(EO) : the former value equals the average number of hydroxylgroups on the anhydroglucose unit which has been substituted by ethylgroups, whereas the latter corresponds to the average total number ofethylene oxide groups substituted on the anhydroglucose unit. Ethyleneoxide (hydroxyethyl) can form short oligo(ethylene oxide) chains andthus MS_(EO) >DS_(EO).

The molecular weight, i.e. the degree of polymerisation (n), of thecellulose ether seems to be less important for obtaining the gellingeffect. This may be because all the employed solutions are semi-dilute,i.e. the cellulose ether concentrations considerably exceed theso-called overlap concentration.

A preferred EHEC to use in a composition of the invention is EHEC ofmedical grade (Berol Nobel, Sweden), that is ethyl hydroxyethylcellulose ethers having a cloud point of 30°-35° C., especially 32°-35°C. These cellulose ethers normally have a DS_(ethyl) of 1.2-2.5 and anMS_(EO) of 0.5-1.5, but they may also contain minor amounts of othersubstituents, such as methyl and hydroxypropyl. The degree ofpolymerisation of said cellulose ether could be 200-600, preferably500-600. The viscosity of said EHEC is 30-400 cP in a 1% aqueoussolution as measured according to Brookfield LV, 12 rpm at 20° C. Themedical grade EHEC is more hydrophobic than the grades of EHEC which arecommercially available today.

Tests have shown that EHEC has bioadhesive properties both in thepresence and absence of surfactants.

The present invention also refers to the use of an aqueous solution ofethyl hydroxyethyl cellulose having a DS_(ethyl) value of 1.2-2.5,MS_(EO) value of 0.5-1.5 and a cloud point of 30°-35° C. as a carrierfor administration of a pharmacologically active substance.

Cellulose ethers are generally nontoxic and high purity grades of mostcommercial products are approved as food additives and for use incosmetics as well as in pharmaceutical compositions.

The surfactant should contain either a positively or a negativelycharged headgroup. Examples of the former surfactants are alkyl ammoniumcompounds (e.g. hexadecyltrimethylammonium, tetradecylbetainate andhexadecylpyridinium salts, e.g. chloride and bromide). Examples of thelatter are alkyl sulphates (sodium dodecyl sulphate), alkyl ethersulphates (sodium dodecyl monoethyleneoxide sulphate), alkyl sulphonates(sodium dodecyl sulphonate), alkyl phosphates (sodium dodecylphosphate), alkyl phosphonates (sodium dodecyl phosphonate),alkylarylsulphonates (sodium p-dodecylbenzene sulphonate) and salts ofsaturated or unsaturated fatty acids (potassium and sodium dodecanoate,tetradecanoate, hexadecanoate, octadecanoate, 9-hexadecenoate,cis-9-octadecenoate). The examples listed above normally contain asingle hydrocarbon chain which should contain between 10 and 20 carbonatoms in order to interact strongly enough with the polymer. Otherexamples are amino acid and carbohydrate based surfactants, e.g. acylglutamates and salts of acyl arginine esters (N-myristoyl-L-arginemethyl ester, hydrochloride), and puranosyl glycerides, respectively.

It is also possible to use ionic double-chained surfactants and lipidswith more than 8 carbons per chain, such as phospholipids (e.g.phosphatidylglycerols, phosphatidyl serins, and phosphatidyl inositols),dialkyl ammonium compounds, dipuranosyldiglycerides (e.g.digalactosyldiglyceride), and Aerosol OT (sodium bis(2-ethylhexyl)sulphosuccinate).

The amount of surfactant is of the same order of magnitude as thecritical micelle concentration in a polymer-free solution. The optimumconcentration of the surfactant in the composition of the invention isin the order of 0.2-5 times the critical micelle concentration.

According to another aspect of the invention the charged surfactant canbe an amphiphilic drug, an ionic drug derivatized with a hydrocarbonchain, saturated or unsaturated, of a length sufficient to cause theEHEC gel to form on temperature increase, or a lipophilic drugderivatized with an ionic group. The derivatized drug is by definition aprodrug. Depending on the nature of the prodrug it may be possible tocontrol the fate of the gel after the prodrug has been converted intoits corresponding parent drug. After the conversion and the release ofthe parent drug the remaining lipophilic part of the prodrug could beeither charged in which case the gel is maintained, or noncharged,leading to the destruction of the gel. For example, if the prodrugconsists of a long aliphatic chain connected to the parent drug via anester bond, the hydrolysate could either consist of the drug and adissociated fatty acid or the drug and a fatty alcohol.

By this the charged surfactant, which is only used to give a gel, andmight not be desirable from a toxicological point of view, can be atleast partly omitted. Other advantages with this system is that therelease of drug can be better controlled; a combination of drug andprodrug can give a bolus and a prolonged effect; and that the drug mightbe better protected from degradation as being adsorbed to EHEC. Thislatter aspect might be important for instance in connection withpropeptides and other prodrugs of macromolecules.

The origin of the gel formation is a strong hydrophobic interactionbetween polymer and surfactant which is cooperative in nature and thusresembles normal micelle formation. Surfactant clusters formed in thisway may then act as cross-links between different polymer chains, givingrise to an extended three-dimensional gel structure. The electrostaticrepulsion between different surfactant clusters may lead to polymerchain expansion which may also contribute to the increase ingelling/viscosity. Furthermore, and most importantly, the hydrophobicattraction between the two species has been shown to be promoted by anincrease in temperature--a surprising experimental fact--explained as aresult of increased hydrophobicity of the polymer upon heating. Thewhole process is reversible: on cooling, the system regains its originalproperties.

It is possible to control the gel formation, both the temperature atwhich maximum viscosity occurs and the strength of the gel, by differentmeans. This is performed by varying the concentration of either thecellulose ether or the surfactant. Alternatively, the gel-formingstrength could be altered by replacing the surfactant with another whichbinds either less or more strongly to the polymer. A more amphiphilicsurfactant, reflected in having a longer alkyl chain and thus a lowercritical micelle concentration, would bind more strongly to the polymerand give rise to a stronger gel on heating at a lower surfactantconcentration than would be produced by a less amphiphilic surfactant.

The ratio of surfactant to cellulose ether should be 1:5 to 1:25 byweight. Generally this ratio is about 1:10. The total concentration ofcellulose ether and surfactant in the composition is comparatively low,it should not exceed 3% by weight and preferably be from 0.5 to 1.5% byweight.

Once the gel is formed it is very resistant to the effects of high saltconcentrations; actually, salt promotes the stability of the gel indifferent ways. Firstly, the adsorption of surfactants on to the polymerchain is favoured by the diminished electrostatic repulsion betweencharged headgroups caused by the added counterions; this leads to adecrease in the concentration of singly dispersed surfactant molecules.Secondly, a high salt content leads to a reduced solubility of thepolymer reflected in increased interpolymer attractions; all in all, thethree-dimensional network built-up by polymer chains and surfactantclusters is strengthened.

However, if salt is present in the polymer solution during thepreparation e.g. in physiological concentrations, higher surfactantconcentrations are necessary.

In accordance with a specific embodiment of the invention the carriercomposition, especially for oral administration also comprises anonionic, low-molecular compound in an effective isotonic concentration,such as sucrose, glucose, glycerol. This produces an isotonic gel whichdoes not undergo shrinkage in a physiological medium.

The carrier composition can in addition contain optional additives knownin the art for improving different aspects of the composition, such asflavouring agents, colorants and preservatives.

At, or below, room temperature, the carrier composition, e.g. awater-based EHEC-surfactant system, is a clear, low-viscous aqueoussolution without unpleasant taste and smell. The water content could beas high as 99 wt %, which means that the carrier composition is easy todrink, instil or spray.

The carrier of the invention can be used for oral or localadministration of a drug or a prodrug to the skin, the mucosa, the eyeor a body cavity such as the mouth, ear, nose, vagina, rectum.

The liquid carrier system has a viscosity that allows spraying,instilling, pouring, drinking or spreading the dosage form into theintended biological cavity or part of the body. Upon administration theliquid carrier composition will adhere to the mucus or the biologicalmembrane and form a high viscosity or gel layer.

Tests in vitro as well as in vive have shown that the composition of theinvention gels in gastric juice and that this gel is also retained inintestinal juice. This implies that on oral administration of a drug ina carrier of the invention a gel will form in the gastrointestinal tractgiving a slow release of the active substance, as well as an improvedbioavailability. In order for a gel to form in the gut a cationicsurfactant or an anionic surfactant not being protonized at low pHshould be used. An anti-asthma drug, such as theofylline, may then beincorporated without affecting the gelling mechanism. Once the gel isformed it is very resistant against salt and mechanical rupture and thegastric emptying time will be prolonged. The diffusion of the drugwithin the gel lump is normally not restricted (except for drugs havinga charge opposite to the surfactant)--instead the border between lowsalt (gel) and high salt (physiological medium) serves a diffusionbarrier.

The inherent bio(muco)adhesive properties of EHEC makes it suitable as aconstituent in saliva substitutes. Objective (friction measurements) andsubjective (questionnaire) efficacy evaluations of EHEC solutions withand without ionic surfactant on patients suffering from xerostomia havebeen performed. It was established that EHEC solutions relieve thesymptoms of mouth dryness, with good lubricating properties. This isexplained as a result of the high water-retaining capacity and gel-likestructure of the EHEC system.

Mucoadhesion studies in vitro (detachment force measurements) have shownthat both EHEC solutions and EHEC-ionic surfactant solutions adherestrongly to a model mucus gel at 37° C.

If the mouth rinse solution contains a suitable anionic surfactant it ispossible to incorporate fluoride ions (F⁻) for anticaries treatment. Thefluoride content (as NaF) could vary between 0.05 and 0.2 wt % withoutaffecting the gelling behaviour significantly if sodium dodecyl sulphate(SDS) is used. After being warmed up in the mouth the solution istransformed to a gel which sticks to the mucous membrane in a thinlayer. The gel could then provide a source of F⁻ ions which are slowlyreleased to the saliva.

The ideal product will have a low viscosity at room temperature so thatit can easily be taken orally. At mouth temperature the product shouldbecome viscous, thus sticking to the palate and gum. However, it shouldnot gel in the mouth, in order to have a high-patient compliance.

When used to treat conditions of the eye, nose or ear the liquid carriermay be administered by any conventional means of delivering dropformulations.

Adding an ionic surfactant to a nonionic cellulose ether solutionimproves the carrier from a bioavailability point of view. Thesurfactant modifies the carrier in that it undergoes a temperaturedependent transformation from a low viscous solution to a solution withhigher viscosity, but still retains its pseudoplastic behaviour. Thismeans that at room temperature the solution is easy to administer as eyedrops since the solution has low viscosity and in contact with the eye(35° C.) will become more gel-like in consistency. The surfactantdecreases the surface tension of the polymer solution and accordinglythe size of administered drops from an eyedrop bottle. This is also anadvantage since numerous studies have shown that the precorneal drainagerate of solutions in the eye increases linearly with instilled volume.In other words, reduction of the instilled volume increases ocular drugavailability.

EHEC shows several advantages over other polymers proposed as ocularvehicles, where increased viscosity is dependent on external factors,such as pH and electrolytes.

Tranexamic acid, used as a haemostatic agent, could be dissolved in anEHEC-surfactant solution to give a highly viscous one-phase system.Typical concentrations of tranexamic acid and EHEC-surfactant are 10 and1 wt %, respectively, which result in an isotonic solution having anappropriate pH of 7. One dose in each nasal cavity (2×100 μl) would thencorrespond to 20 mg tranexamic acid. After being applied in a drop,either by using a single unit dose pack or a pipette, the solutionstiffens which thereby prolongs the action of the drug. The sameprinciple of mixing tranexamic acid with EHEC-surfactant solution couldbe used for any local haemostatic treatment, e.g. gastric or coloniculcer.

Polypeptides and polysaccharides could also be administered by means ofthe EHEC thermogel vehicle. Nasal delivery of insulin may serve as anexample. EHEC-surfactant formulations, containing therapeutic relevantconcentrations of insulin, improve the absorption of insulin due to theincreased contact time between mucus and the drug. This has beenestablished by measurements of the blood glucose level in rats.Furthermore, release profiles in vitro confirm that also macromoleculescould be efficiently sustained when using the thermogel system based onEHEC and ionic surfactant. The role of the surfactant is, besides takingpart in the gel structure, to enhance the penetration of drug throughthe mucous membrane. Another advantage of this system is the fact thatthe gel does not undergo phase separation as other thermoreversiblepolymer systems do. The ability of the EHEC-surfactant gel to maintainits water content after being applied may facilitate the penetration.

When used for rectal, urethral or vaginal administration, the liquidcarrier is administered by any conventional means, e.g. a syringe.

The bioadhesion properties will make the drug stay in contact with thetissue for a longer time.

Local administration can be made to serve the purpose of enhancedsystemic absorption. One goal could be to avoid first pass metabolism.

The drug release can be controlled within certain limits to permit amore even blood concentration level. It can make it possible to reducethe number of administrations and increase compliance.

The pharmaceutical composition of the invention which is a liquid at andbelow room temperature and forms a high viscosity layer or gel at bodytemperature comprises a pharmacologically active substance incombination with a carrier composition as described above.

Any pharmacologically active material which is water-soluble may bedelivered in the drug delivery system of this invention. Preferably thedrug is noncharged. Salts of a drug could also be used even if this mayrequire higher surfactant concentrations. In this respect it may be moreadvantageous to use the noncharged form, e.g. the base form of anamine-containing drug instead of its corresponding salt, provided thebase is soluble in water.

If incorporating a salt, regardless of being organic or inorganic, anupper limit in concentration exists. High salt concentrations during themixing procedure lead to precipitation of the liquid drug carrier whichthus limits its applicability to high drug loading. However, theincreased contact time and improved drug uptake from the liquid drugcarrier compared with an aqueous solution means that a lower drugconcentration could be used.

The drug may also be insoluble in water and can be suspended in the drugdelivery system. Both the polymer and the surfactant are amphiphilic innature and adsorb on to solid particles and alone protect fromsedimentation. The present invention provides an even better stabilizingeffect when finely ground particles are suspended since the carriersystem is a combination of polymer and ionic surfactant.

According to a specific embodiment of the pharmaceutical composition thecharged surfactant could be replaced, in part or in total, by anamphiphilic drug.

The preparation of the liquid drug carrier is described below and theappropriate examples which follow were all performed according to thisprocedure. The polymeric component of the liquid carrier systemdissolves better at low temperatures and thus the polymer is dispersedin warm water to avoid lump formation and then preferably put in a coldplace, such as a refrigerator or thermostated container. The mixtureshould be stirred to facilitate the dissolution of the polymer. Thewhole procedure is completed within 2 h but normally the solution isaged overnight in a cold place. The second component of the liquidcarrier, the ionic surfactant is then added in appropriate amounts,generally in a ratio of surfactant to polymer of about 1:10 by weight.

The drug substance and various additives such as preservatives andnonionic, low-molecular compounds in an effective isotonic concentrationare then added.

Drugs which can be administered in the drug delivery system of thepresent invention are

antibacterial substances such as p-aminosalicylic acid, N-formamidoylthienamycin, penicillin, tetracycline, chloramphenicol, neomycin,bacitracin, and the like; sulfamethazine, sulfanilic acid,sulfaphenazole, sulfasymazine, sulfamoxole, sulfamipyrine and the like;

aminoglycoside antibiotics such as gentamycin, kanamycin, amikacin,sisomicin and tobramycin and the like; norfloxacin and the like;

antihistaminics and decongestants such as pyrilamine, pheniraminemaleate, zolamine, antazoline and the like;

anti-inflammatory substances such as corticosteorids, such as cortisone,hydrocortisone, hydrocortisone sodium succinate, hydrocortisone sodiumphosphate, prednisolon, methylprednisolon, triamcinolon, dexamethasone,budesonide; phenybutazone, ibuprofen, indomethacin and its salts,sulindac, allopurinol, oxyphenbutazone and the like;

various peptide hormones such as insulin, somatostatin and analogues ofthose drugs, and the like; antiparasitic compounds such as ivermectin;

antiviral compounds such as acyclovir and interferon;

analgesics such as aspirin, salicylic acid, diflunisal, morphine and itssalts and the like;

antiseptic substances such as cetylpyridinium chloride, benzalkoniumchloride, chlorhexidine and the like;

antimycotic substances such as cetyltrimethylammonium bromide and thelike;

antifungals such as polyoxyethylene nonylphenols, alkylaryl sulfonates,miconazole nitrate, metronidazole, trimethoprim and the like;

antiprotozoals such as chloramphenicol, sulfamethoxazole and the like;

local anesthetics such as salts of procaine, benzocaine, lidocain,procain, bupivacaine, tetracain, xylocaine, mepivacaine and their saltsand the like;

antiasthma drugs such as adrenaline, ephedrine, epinephrine,aminophylline, theophylline and the like;

urinary tract disinfectives such as trimethroprim, nitrofurantoin,norfloxacin and the like;

anticoagulants such as heparin and its salts, such as calcium and sodiumheparin, bishydroxycoumarin and the like;

anticonvulsants such as diazepam, sodium phenytoin and the like;

antidiabetics such as insulin, tolbutamide, somatostatin and itsanalogs, tolazanide, acetohexamide, chlorpropamide and the like;

antihypertensive such as methyldopa, hydralazine, clonidine,chlorothiazide, timolol, propanolol, metroprolol, prazosinhydrochloride, furosemide and the like;

muscle relaxants such as succinylcholine chloride, danbrolene,cyclobenzaprine, methocarbamol, diazepam and the like;

vitamins such as B₆, B₁₂ and C and the like;

diagnostic aids such as sodium oleate and the like (pancreatic function)and the like;

contrast media such as BaSO₄, iohexol and other iodine-containingsubstances and the like (x-ray), iron(II,III)oxide particles and otherferromagnetic materials (magnetic resonance imaging).

EXAMPLES

Nonionic cellulose derivatives and ionic surfactants are mixed in waterto give a relatively easily flowing solution at room temperature. Thesurfactants could either be negatively or positively charged. If such asystem, containing appropriate types and amounts of cellulose ether andcosolutes, is heated to 30°-42° C., in particular 37° C., itsrheological properties will be drastically changed, leading to thereversible formation of a stiff and transparent gel. Representativesystems are described below.

It is also demonstrated that nonionic cellulose derivatives having acloud point over 35° C. do not form a gel at body temperature.

In the following examples the viscosity values, n, refer to steady-flowviscosity measured on a Bohlin VOR rheometer Bohlin Reologi, Lund,Sweden), measuring system: C 25; torque element: 21.6 g cm (orequivalent), at the stated shear rate.

The cloud point, (CP; flocculation or phase separation temperature) hasbeen determined for a 1.0 wt % solution of the cellulose ether in water,heated at a rate of 10° C./min, on a Mettler FP5+FP51 spectrophotometer.In the following tests and examples all percentages refer to percent byweight.

The tests in the examples below were performed with ethyl hydroxyethylcellulose, EHEC, of different qualities, i.e.:

    ______________________________________                                                   DS.sub.ethyl                                                                         MS.sub.EO                                                                             CP, °C.                                                                          η, mPas                               ______________________________________                                        EHEC A       1.7      1.0     34.0    42                                      EHEC B       1.9      1.3     34.4    89                                      EHEC Bermocoll ®                                                                       1.5      0.7     35.9    40                                      CST 103 Batch 1                                                               EHEC Bermocoll ®                                                                       1.5      0.7     36.8    46                                      CST 103 Batch 2                                                               EHEC Bermocoll ®                                                                       0.8      0.8     63      40                                      E230 G                                                                        ______________________________________                                    

Viscosity values (η) were measured on 1% aqueous solutions at a shearrate of 7.31 s⁻¹ at 20° C.;

    __________________________________________________________________________    Example 1                                                                     Composition                    Concentration, %                               __________________________________________________________________________    Ethyl hydroxyethyl cellulose (EHEC A)                                                                        0.75                                           Tetradecyl betainate (TDB; tetradecyloxycarbonyl-                                                            0.15                                           N,N,N,-trimethylmethanaminium chloride (Berol Nobel))                         Water, deionized               99.1                                           Viscosity at different temperatures                                           Temperature*, °C.                                                                      20                                                                              25     30 35      37  40                                    η**, mPas  130                                                                              1,100  6,600                                                                            72,000  46,000                                                                            27,000                                *dT/dt = 2° C./min                                                     **Shear rate 0.233 s.sup.-1                                                   Viscosity at different concentrations of surfactant                                                   η*, mPas                                                  TDB conc., %    20° C.                                                                     37° C.**                                   __________________________________________________________________________            0               25                                                            0.10            74  73,000                                                    0.12            93  54,000                                                    0.15            130 15,000                                            *Shear rate 0.233 s.sup.-1                                                    **Thermal equilibrium time 8 min                                              Example 2                                                                            Composition         Concentration, %                                   __________________________________________________________________________           Ethyl hydroxyethyl cellulose (EHEC B)                                                             1.0                                                       Sodium dodecyl sulphate (SDS)                                                                     0.09                                                      Water, deionized    98.91                                              Viscosity at different temperatures                                           Temperature °C.                                                                  20.1                                                                             25.3                                                                             30.4                                                                             33.3                                                                             35.0                                                                             36.8                                                                             37.5                                                                             38.3                                                                             39.0                                                                             39.8                                                                              42.3                                                                              42.3                             η**, Pas                                                                            0.32                                                                             0.47                                                                             1.21                                                                             2.70                                                                             5.56                                                                             15.5                                                                             39.2                                                                             66.0                                                                             90.4                                                                             114 130 111                              *dT/dt = 1° C./min                                                     **Shear rate 0.216 s.sup.-1                                                   Viscosity at different concentrations of surfactant                                                   η*, mPas                                                  SDS conc., %    20° C.                                                                     37° C.                                     __________________________________________________________________________            0.09            147 108,000                                                   0.12            500 86,000                                                    0.14            1,290                                                                             36,000                                            *Shear rate 0.216 s.sup.-1                                                    **Thermal equilibrium time 8 min                                              Example 3                                                                     Composition                Concentration, %                                   __________________________________________________________________________    Ethyl hydroxyethyl cellulose (EHEC B)                                                                    1.0                                                Cetyltrimethylammonium bromide (CTAB)                                                                    0.15-0.22                                          Water, deionized           99.85-98.78                                        Viscosity at different concentrations of surfactant                                                   η*, mPas                                                  CTAB conc., %   20° C.                                                                     37° C.                                     __________________________________________________________________________            0.15            194 10,500                                                    0.18            270 8,200                                                     0.22            296 8,200                                             *Shear rate 0.216 s.sup.-1                                                    **Thermal equilibrium time 8 min                                              Example 4                                                                     Composition                Concentration, %                                   __________________________________________________________________________    Ethyl hydroxyethyl cellulose (EHEC B)                                                                    0.85                                               Sodium oleate              0.05                                               Water, deionized           99.1                                               Viscosity at different temperatures                                           Temperature*, °C.                                                                20.2 24.3                                                                              30.2 31.8                                                                              33.3                                                                              34.7                                                                             36.2                                                                              37.4                                                                             41.1                                                                              44.3                            η**, Pas                                                                            <0.3 <0.3                                                                              <0.3 <0.3                                                                              0.4 0.7                                                                              1.3 3.0                                                                              14.6                                                                              71.9                            *dT/dt = 1° C./min                                                     **Shear rate 0.233 s.sup.-1                                                   COMPARATIVE EXAMPLES                                                          Example 5                                                                            Composition     Concentration, %                                       __________________________________________________________________________           Ethyl hydroxyethyl cellulose                                                                  0.85                                                          (Bermocoll ® CST 103 Batch 1)                                             Sodium oleate   0.05                                                          Water, deionized                                                                              99.1                                                   Viscosity at different temperatures                                           Temperature*, °C.                                                                19.9 24.3                                                                              30.3                                                                              32.3 34.2                                                                              36.1                                                                             37.8                                                                              39.3                                                                             42.4                                                                             44.4                             η**, Pas                                                                            <0.3 <0.3                                                                              <0.3                                                                              <0.3 <0.3                                                                              0.4                                                                              0.5 0.8                                                                              2.0                                                                              14.1                             *dT/dt = 1° C./min                                                     **Shear rate 0.233 s.sup.-1                                                   Example 6                                                                     Composition                   Concentration, %                                __________________________________________________________________________    Ethyl hydroxyethyl cellulose (Bermocoll ® E230 G)                                                       0.85                                            Sodium oleate                 0.05                                            Water, deionized              99.1                                            Viscosity at different temperatures                                           Temperature*, °C.                                                                20.1                                                                             24.3                                                                              30.2                                                                              31.9                                                                              33.4                                                                              34.9                                                                              36.2                                                                              37.7                                                                              41.5                                                                              44.3                             η**, Pas                                                                            0.3                                                                              <0.3                                                                              <0.3                                                                              <0.3                                                                              <0.3                                                                              <0.3                                                                              <0.3                                                                              <0.3                                                                              <0.3                                                                              <0.3                             __________________________________________________________________________     *dT/dt = 1° C./min                                                     **Shear rate 0.233 s.sup.-1                                              

These examples show that compositions based on ethyl hydroxyethylcelluloses with a CP higher than 35° C. do not form a gel at bodytemperature.

When EHEC Bermocoll® CST 103, Batches 1 and 2, respectively, werecombined with SDS and water, as described in Example 2, no gellingoccurred after heating as confirmed by ocular inspection.

TEST ON GEL FORMATION IN GASTRIC JUICE IN VITRO

The gel forming ability in vitro in simulated gastric juice has beentested for a composition according to the invention, a solution of 0.85%EHEC B+2.6% glycerol+0.087% SDS in water.

The gastric juice solution is prepared according the recipe in USP XXII:pepsin (3.2 g), dissolved in hydrochloric acid (7.0 ml), and sodiumchloride (2.0 g) are mixed and dissolved in 1000 ml water. 25 ml of thesolution is transferred to a container immersed in a thermostat bath(37° C). 5 ml of the polymer solution/dispersion to be tested is thengently added to the gastric juice solution without stirring and thesystem is then visually examined.

A gel is formed and there is no appreciable change in size after 1 h.The gel has a somewhat milky appearance due to the high ionic strengthof the gastric juice which leads to partial phase separation on thesurface of the gel lump. Cooling to room temperature leads to a completemixing and disappearance of the gel.

TEST ON GEL MAINTENANCE IN INTESTINAL JUICE IN VITRO

A simulated intestinal juice was prepared as follows in accordance withUSP XXII: KH₂ PO₄ (6.8 g) is dissolved in deionized water (250 ml). 0.2MNaOH (190 ml) and deionized water (400 ml) are then added and mixed. Tothis solution pankreatin (10.0 g) is added and the pH is adjusted to7.5±0.1 with 0.2M NaOH. The final volume (1000 ml) is adjusted withwater.

The gel formed in the gastric juice system above was after 2 htransferred to the simulated intestinal juice, heated to 37° C. The gelwas maintained in the new environment for at least 22 h. The volume ofthe gel lump was only reduced by ca 50%.

PHARMACEUTICAL COMPOSITIONS

A nonionic cellulose ether (EHEC) and ionic surfactants are mixed inwater to give a relatively easily flowing solution at room temperature.A biologically, that is pharmacologically, active component, e.g. adrug, which could either be hydrophilic (charged or noncharged),hydrophobic or amphiphilic in nature, is added to the mixture.Alternatively, the surfactant could be replaced by the drug if thelatter is strongly amphiphilic in character. If such a system,containing appropriate types and amounts of EHEC and cosolutes, isheated to 30°-42° C., in particular to 37° C., its rheologicalproperties are drastically changed, leading to the (reversible)formation of a stiff and transparent gel. The EHEC polymer withoutsurfactant is also an excellent excipient in pharmaceuticalformulations, owing to its thickening, emulsion stabilizing, as well asadhesive properties.

    ______________________________________                                        Oral composition                                                              Antiasthmatic composition                                                                       Concentration, %                                            ______________________________________                                        EHEC of medical grade                                                                           1.0                                                         Sodium dodecyl sulphate                                                                         0.087                                                       Theofylline       0.080                                                       Water, purified   98.8                                                        Buccal composition I                                                          Anti-caries composition                                                                         Concentration, %                                            ______________________________________                                        EHEC of medical grade                                                                           0.50                                                        Sodium dodecyl sulphate                                                                         0.174                                                       Sodium fluoride   0.05                                                        Water, purified   99.3                                                        ______________________________________                                    

The NaF concentration could range from 0.05 to 0.5%. At most the SDSconcentration is 0.35% (for 0.75% EHEC). An increase in SDS contentdecreases the ability of the teeth to adsorb F⁻ and therefore a low SDScontent is desirable. Compared to toothpastes the SDS content requiredin these EHEC systems is very small (normally the SDS content variesbetween 0.5 and 2%).

    ______________________________________                                        Buccal composition II                                                         Antifungoid mouth wash                                                                              Concentration, %                                        ______________________________________                                        EHEC of medical grade 0.85                                                    Hydroxypropyl-β-cyclodextrin (Aldrich)                                                         5.0                                                     Hydrocortisone        0.6                                                     Water, purified       93.6                                                    ______________________________________                                    

The composition is a clear, low-viscous solution with a high drug loadwhich is easy to apply. Hydrocortisone is normally administered as anointment or a cream--administration forms which are difficult to applyin the mouth and which are also unpleasant to use. The most importantadvantage of this formulation is that it adheres to the mucous membrane,has a high water holding capacity and thus relieves xerostomia which isthe usual cause of fungoid growth.

    ______________________________________                                        Dermal composition I                                                          Analgetic composition                                                                           Concentration, %                                            ______________________________________                                        EHEC of medical grade                                                                           0.75                                                        Sodium dodecyl sulphate                                                                         0.087                                                       Salicylic acid    0.1                                                         Water, purified   99.1                                                        Dermal composition II                                                         Antiseptic composition                                                                          Concentration, %                                            ______________________________________                                        EHEC of medical grade                                                                           1.0                                                         Benzalkonium chloride                                                                           0.4                                                         Water, purified   98.6                                                        Dermal composition III                                                        Antimycotic composition                                                                         Concentration, %                                            ______________________________________                                        EHEC of medical grade                                                                           0.75                                                        Cetylpyridinium chloride                                                                        0.1                                                         Water, purified   99.15                                                       ______________________________________                                    

Ocular composition

Three different solutions were prepared from the following constituents:EHEC of medical grade, tetradecyl betainate (TDB), timolol hydrogenmaleate (TM; Sigma) and purified water.

    ______________________________________                                        Antiglaucoma composition (%)                                                  System       EHEC    TDB       TM   Water                                     ______________________________________                                        0.34% TM (aq)                                                                              --      --        0.34 99.66                                     1            1.0     0.475     0.34  98.185                                   2            2.0     0.930     0.34 96.73                                     Nasal composition I                                                           Nasal decongestant composition                                                                       Concentration, %                                       ______________________________________                                        EHEC of medical grade  1.10                                                   Cetyltrimethylammonium bromide                                                                       0.109                                                  Oxymethazoline-HCl     0.018                                                  Water, purified        98.9                                                   Nasal composition II                                                          Haemostatic composition                                                                              Concentration, %                                       ______________________________________                                        EHEC of medical grade  1.0                                                    Sodium dodecyl sulphate                                                                              0.087                                                  Tranexamic acid        10.0                                                   Water, purified        89.9                                                   Nasal composition III                                                         Antidiabetic composition                                                                             μl                                                  ______________________________________                                        1% aqueous EHEC solution                                                                             800                                                    with 0.087% sodium dodecyl sulphate                                           Insulin (Actrapid ® Human)                                                                       100                                                    Purified water         100                                                    Rectal Composition I                                                          Anti-inflammatory composition                                                                        Concentraton, %                                        ______________________________________                                        EHEC of medical grade  1.0                                                    SDS                    0.087                                                  Prednisolone           0.1                                                    Water                  98.8                                                   Rectal Composition II                                                         Anti-inflammatory composition                                                                        Concentration, %                                       ______________________________________                                        EHEC of medical grade  1.0                                                    SDS                    0.087                                                  Budesonide             0.01                                                   Water                  98.9                                                   ______________________________________                                    

Surprisingly, both water-insoluble (budesonide) and very slightlysoluble (prednisolon) drug substances can be successfully incorporatedin the carrier system without affecting the thermogelling effect asjudged from visual inspection after heating the suspension to 37° C.Furthermore, and most importantly, the suspensions are stable duringlong periods of storage; e.g. Rectal composition II (budesonide) wasstored for 8 months at room temperature without any sediments beingobserved on the bottom of the test tube.

TEST ON RELEASE IN VITRO Test of the ocular composition

In order to demonstrate the ability to sustain the in vitro release oftimolol maleate from the gel-forming EHEC-charged surfactant system, theOcular composition, described above was studied in a USP paddleapparatus (Dissolutest, Prolabo), connected to a spectrophotometer(Lambda 2, Perkin-Elmer).

Samples of the three ocular solutions were poured into plexiglass cupswith a 4.0 ml cylindrical bore (diffusion surface 21.24 cm²). The cupswere covered with nylon bolting cloth (mesh size 80 DIN) to keep the gelsamples in place during the test. Cups filled with sample solution wereincubated at 40° C. for 15 min immediately before the test. This inducedgel formation in systems 1 and 2. The test was started when the cups hadbeen immersed in the medium in the apparatus and the paddles had startedto rotate.

The release of timolol maleate was detected spectrophotometrically. Thefollowing test parameters were used in the test

Sample volume: 4.0 g (filled cups)

Medium: 500 ml 8.15 mmolar NaCl(aq), isotonic with 0.34% TM

Temperature: 37.0°±0.3° C.

Paddle speed: 20 rpm

Wavelength: 295.0 nm, UV lamp

Background corr.: before every measurement cycle

Spect. reference: pure medium

Pump speed: 99 (maximal speed for the peristaltic pump,

Ismatech IPN-16, Labinette)

The test results, which are plotted in FIG. 1, clearly reveal thedifference in release rate of timolol from the 0.34% aqueous referencesolution and the two gelled EHEC-ionic surfactant systems.

Test of the Nasal composition III

In order to demonstrate the in vitro release profile of insulin from thecarrier system of the invention, the following diffusion model was used.

To the donor compartment of a diffusion apparatus comprising a donorcompartment, a receiving compartment, a membrane, and a sampling site,thermostated at 37° C., was added 1 ml of the composition. Sampling fromthe receiving compartment was made after 3, 5, 10, 15, 30, 60, 120 and180 min. The insulin content was analysed according to the Folin-Lowrymethod.

The test results with the Nasal composition III (circles) as well asCarbopol® 934P, crosslinked poly(acrylic acid) (squares) are given inFIG. 2.

TESTS IN VIVO Release of insulin in rat

The efficiency of a carrier composition of the invention was tested bynasal administration of insulin to anaesthetised rats, in which thearteria carotis had been catheterized and trachea tubings inserted, andsubsequent measurement of the blood glucose level.

The Nasal composition III, as described above, as well as a referencesystem based on 0.5% Carbopol® 934P in water, were administrated via thenostril, through a polyethylene catheter and an automatic pipette in adose of 1 IU insulin/kg. Carbopol, a crosslinked poly(acrylic acid), isa viscosity-increasing polymer with bioadhesive properties which iscommonly used as a carrier in drug delivery systems. The insulin contentboth in the composition of the invention and in the reference solutionwas 10 IU/ml.

Blood samples were collected after 3, 5, 10, 15, 30, 60, 120, 180 and240 minutes and the glucose levels were enzymatically assayed on aBeckman DRISTAT.

The results are given in FIG. 3 (Circles: Nasal composition III;Squares: Carbopol® solution). The test in vitro as well as the test invivo both show that the EHEC-SDS system is equivalent to the Carbopolsystem as to release and delivery of insulin.

Effect on xerostomia in man

Xerostomia, mouth dryness, implies a decrease of saliva secretion thatmay cause an impairment of the mucous barrier protective properties.Xerostomia may have many causes. For relieving some of the problemsrelated to xerostomia many patients use saliva substitutes containingbioadhesive polymers, e.g. sodium carboxymethyl cellulose and mucin.

A new technique has been developed for evaluating oral mucosal dryness.An instrument comprising a probe measures the mucosal slide friction andthe lubrication properties of different bioadhesive formulations (V.Henricson, A. Svensson, H. Olsson, T. Axell: Evaluation of a new devicefor measuring oral mucosal surface friction, 1990, Scand. J. Dental Res.98, 529-536).

The lubrication properties of saliva substitutes based on mucin, sodiumcarboxymethyl cellulose and EHEC and of water have been evaluated byusing this technique.

Six patients with xerostomia (average age 73 years) were selected forthe study. All of them suffered from xerostomia and the condition wasrelated to salivary gland diseases. Three suffered from documentedSjogren's syndrome, fulfilling the Copenhagen criteria, and the otherthree showed unspecific sialoadenitis at biopsy. All six patients showeda mixed salivary flow rate below 1.5 ml/15 min at rest. No one had anyclinically visible mucosal lesions. None of the patients used drugs on aregular basis or smoked tobacco.

The patients were asked not to drink or eat anything during the lasthour before the start of the experiment. Before rinsing, a basalfriction value of lip mucosa was registered with the probe. Thereafter,the patients rinsed the mouth during one minute with 15 ml testsolution. The friction value of the lip was then measured with the probeapproximately every fifth minute until the basal value wasre-established. The effect was defined as the time in min which elapsedfrom the end of the rinsing and until the basal value was recorded.

    ______________________________________                                        Results                                                                       Saliva substitute     Mean value, min                                         ______________________________________                                        Saliva Orthana ®* 11                                                      1.0% sodium carboxymethyl cellulose                                                                 16                                                      1.0% EHEC             15                                                      0.75% EHEC + 0.10% CTAB                                                                             19                                                      0.75% EHEC + 0.115% SDS                                                                             11                                                      Pure Water             6                                                      ______________________________________                                         *Saliva substitute containing 3.5% mucin, from A/S Orthana Kemisk Fabrik,     Kastrup, DK?                                                             

All saliva substitutes showed almost the same lubrication effect on theoral mucosal friction. This effect lasted about twice as long as forwater. This means that the EHEC compositions in these studies havelubrication and bioadhesive properties that are equal to that of thewell-known bioadhesive polymers mucin and sodium carboxymethylcellulose.

MUCOADHESION STUDIES IN VITRO

The mucoadhesive properties of different carrier compositions wereinvestigated by comparison of the mean peak detachment forces recordedwhen samples were separated from a model mucus gel (I. W. Kellaway inBioadhesion and Future Trends, H. E. Junginger and R. Gurny, Eds,Wissenschaftliche Verlags GmbH, Stuttgart 1990).

The tests were performed with the following EHEC qualities:

    ______________________________________                                                CP, °C.                                                                            MS.sub.EO                                                                             DS.sub.ethyl                                      ______________________________________                                        EHEC C    37.0          0.9     1.4                                           EHEC D    32.0          1.1     1.7                                           ______________________________________                                    

Mucoadhesion measurement

The mucoadhesion testing was performed as follows. The mucus gel washeld on an evacuated probe. A lower cell held the test composition andwas sealed to allow the chamber beneath to be evacuated. The cell wasplaced on a balance pan and tared. The probe was lowered onto thecomposition at a constant rate (3.27 mm/min) to a specified loading (10g), the formulation was then separated from the mucus gel (3.27 mm/min).This was repeated five times for each sample of mucus and composition.Data output was stored in a computer for subsequent analysis. Tofacilitate testing at the specified temperatures the balance wasinsulated and heated with an electrical element fitted with a rheostat.

Model mucus gel

Purified porcine gastric mucin (BDH) 0.2 g was hydrated with pH 7.4buffer (0.8 ml). At this concentration the visco-elastic properties ofthe gel approximated those of porcine gastric mucus purified in-house.Stock batches were made up so that each composition was tested withmucus from the same batch. 0.1 g samples of the mucus gel were weighedonto an ultra filtration membrane (22 mm diameter), and brought toexperimental temperature in the balance. The samples were placed on theprobe, held by vacuum and spread to give a uniform surface.

Test formulations

Test compositions according to below were refrigerated (<8° C.), thesample bottles were vigorously shaken and brought to room temperatureprior to use. For each test 400 μl of the composition was carefullypipetted to avoid air entrapment on to an ultrafiltration membrane onthe cell and held in place by vacuum. The cell was then brought toexperimental temperature in the balance. The nature of the compositionsallowed them to flow and cover the membrane with a thin even layer.

Compositions

1. 1.25% sodium carboxymethyl cellulose (Cekol® MVG; Billerud, Sweden)

2. 1.25% EHEC C

3. 1.25% EHEC C+0.115% SDS

4. 1.25% EHEC D

5. 1.25% EHEC D+0.115% SDS

Results

Results are summarized in the following table showing the mean peakdetachment forces (±standard deviation) required for separating thecompositions 1-5 from the mucus gel at 37° C.

    ______________________________________                                        Com-                                                                          position                                                                             1       2       3      4       5                                       ______________________________________                                        Run 1  8.06 ±                                                                             9.30 ±                                                                             9.78 ±                                                                            7.72 ± 0.59                                                                        10.45 ± 1.52                                0.74    1.54    2.00                                                   Run 2  8.82 ±                                                                             8.61 ±                                                                             8.24 ±                                                                            7.77 ± 0.65                                                                         9.43 ± 0.59                                0.46    1.74    0.32                                                   ______________________________________                                    

Conclusions

All test compositions were mucoadhesive, however statistical analysis ofthe mean peak detachment forces established that significant differencesexisted between the compositions. Duncans multiple comparison testindicated that composition 5 required a significantly greater force fordetachment than composition 4. In addition the performance ofcomposition 5 appeared to be superior to that of 1, 2 and 3 althoughstatistically there were no proven differences.

These studies show that both EHEC and the carrier system of theinvention are bio(muco)adhesive. It could also be concluded that theaddition of a charged surfactant improves the bioadhesive properties ofthe cellulose ether.

We claim:
 1. A carrier composition which is a liquid at or below roomtemperature and forms a high viscosity layer or gel at body temperature,characterized in comprising a water-soluble, nonionic cellulose etherhaving a cloud point not higher than 40° C., a charged surfactant andoptional additives in water wherein said optional additives are selectedfrom the group consisting of flavoring agents, colorants, preservatives,isotonic agents and mixtures thereof, and in that the combinedconcentration of the water-soluble, nonionic cellulose ether and thesurfactant is below 3% by weight, and wherein the remainder of thecomposition is water and said optional additives.
 2. A carriercomposition according to claim 1, wherein the water-soluble, nonioniccellulose ether has a cloud point not higher than 35° C.
 3. A carriercomposition according to claim 1, wherein the water-soluble nonioniccellulose ether is an alkyl hydroxyalkyl cellulose, the alkyl groups ofwhich have from 1 to 4 carbon atoms.
 4. A carrier composition accordingto claim 1, wherein the water-soluble nonionic cellulose ether is ethylhydroxyethyl cellulose with a DS_(ethyl) value of 1.2-2.5, a MS_(EO)value of 0.5-1.5 and a cloud point of 30°-35° C.
 5. A carriercomposition according to claim 1, wherein the charged surfactant has apositively or negatively charged headgroup and a hydrocarbon chain offrom 10 to
 20. 6. A carrier composition according to claim 1, whereinthe charged surfactant comprises a prodrug.
 7. A carrier compositionaccording to claim 1 for oral or local administration of a drug and/or aprodrug to the skin, the mucous membrane, the eye or a body cavity.
 8. Apharmaceutical composition which is liquid at and below room temperatureand forms a high viscosity layer or gel at body temperature,characterized in comprising a pharmacologically active substance incombination with a carrier composition according to claim
 6. 9. Apharmaceutical composition which is liquid at and below room temperatureand forms a high viscosity layer or gel at body temperature,characterized in comprising a water-soluble, nonionic cellulose etherhaving a cloud point not higher than 40° C., an amphiphilic drug andoptional additives in water, wherein said optional additives areselected from the group consisting of flavoring agents, colorants,preservatives, isotonic agents and mixtures thereof, and wherein thecombined concentration of the water-soluble, nonionic cellulose etherand the surfactant is below 3% by weight, and wherein the remainder ofthe composition is water and said optional additives.
 10. A carriercomposition according to claim 2, wherein the water-soluble nonioniccellulose ether is an alkyl hydroxyalkyl cellulose, the alkyl groups ofwhich have from 1 to 4 carbon atoms.
 11. A carrier composition accordingto claim 2, wherein the water-soluble nonionic cellulose ether is ethylhydroxyethyl cellulose with a DS_(ethyl) value of 1.2-2.5, a MS_(EO)value of 0.5-1.5 and a cloud point of 30°-35° C.
 12. A carriercomposition according to claim 2, wherein the charged surfactant has apositively or negatively charged headgroup and a hydrocarbon chain offrom 10 to 20 carbon atoms.
 13. A carrier composition according to claim2, wherein the charged surfactant comprises a prodrug.
 14. A carriercomposition according to claim 2 for oral or local administration of adrug and/or a prodrug to the skin, the mucous membrane, the eye or abody cavity.
 15. A pharmaceutical composition which is liquid at andbelow room temperature and forms a high viscosity layer or gel at bodytemperature, characterized in comprising a pharmacologically activesubstance in combination with a carrier composition according to claim2.
 16. A carrier composition according to claim 1 wherein theconcentration of the water-soluble, nonionic cellulose ether andsurfactant is 0.5-1.5% by weight.
 17. A carrier composition according toclaim 5 wherein said hydrocarbon chain has 12 to 18 carbon atoms. 18.The composition of claim 1 wherein said optional additives include anonionic, low-molecular weight compound in an effective isotonicconcentration.
 19. The composition of claim 1 wherein said low-molecularweight compound is selected from the group consisting of sucrose,glucose and glycerol.
 20. The composition of claim 1 wherein saidoptional additives comprise a member selected from the group consistingof flavoring agent, colorant and preservative.